Esmolol hydrochloride is a short-acting beta-blocker used for treatment or prophylaxis of cardiac disorders in mammals. Most of the currently available beta-blockers are stable drugs which can be administered to cardiac patients over relatively long periods of time. However, it is often desirable in the critical care setting to quickly reduce heart work or improve rhythmicity during a cardiac crisis, e.g., during or shortly after a myocardial infarction. Conventional beta-blocking agents can be employed for such treatment, but their long durations of action can cause undesirable side effects.
Esmolol hydrochloride contains an ester functional group and possesses the typical beta-adrenergic blocking activity. However, it differs from conventional beta-blocking compound in that esmolol hydrochloride has a short duration in vivo due to the presence of the ester group. Thus, esmolol hydrochloride is advantageous compared to the conventional beta-blockers because of its unique short-acting activity. However, the ester group in esmolol hydrochloride is found to be unstable in an aqueous environment because of it extreme susceptibility to hydrolytic degradation.
The stability of esmolol in water is mediated by the rate of acid/base hydrolysis of the labile aliphatic methyl ester group. In the past, the rate of degradation of esmolol hydrochloride has been reduced by the use of acetate as a buffer, maintaining the pH as close to 5.0 as possible, minimizing the concentration of esmolol in the solution, and minimizing the concentration of buffer used. Prior art formulations maintain a reasonably long shelf-life, however, they are packaged in glass vials or ampules, and suffer from severe degradation upon autoclaving. As a result, prior art formulations are prepared aseptically. C.f. U.S. Pat. No. 4,857,552. However, terminal sterilization is typically preferred by regulatory authorities as a way of reducing microbiological burden and to ensure the safety of the finished product.
In addition, the formulation disclosed in U.S. Pat. No. 4,857,552 is a small volume injectable formulation. For the purposes of intravenous infusion, the disclosed formulation must be further diluted in pharmaceutically acceptable diluents prior to use. This creates a potential opportunity for calculation or dilution error in a hospital setting. Additionally, microbiological contamination of the product during dilution/aseptic handling is of primary concern. Therefore, there remains a need for a ready-to-use large volume parenteral esmolol hydrochloride that is microbiologically safe and stable in vitro during storage.